The cephalosporin antibiotics have recently achieved considerable success as therapeutic agents for the treatment of infectious diseases of man. This class of antibiotics is produced by two known general methods. In the first of these methods, cephalosporin C is produced by culturing the organism Cephalosporium acremonium, Newton and Abraham, Biochem. J., 62, 651 (1956). Cleavage of the .alpha.-aminoadipoyl side chain of cephalosporin C according to the method described in U.S. Pat. No. 3,188,311 affords 7-aminocephalosporanic acid (7-ACA). Acylation of 7-ACA with an appropriate acyl halide, as, for example, thiophene-2-acetyl chloride, yields the expected 7-acylamidocephalosporanic acid antibiotic. The cephalosporin antibiotics obtained from cephalosporin C according to this method are derivatives of cephalosporanic acid which possesses an acetoxymethyl group attached at the 3-position of the cephalosporin nucleus. According to the cephem nomenclature system for the cephalosporins, the cephalosporin antibiotics obtained from cephalosporin C are named 7-acylamido-3-acetoxymethyl-3-cephem-4-carboxylic acids.
The second method by which the cephalosporin antibiotics are produced involves the chemical conversion of a penicillin antibiotic. This method, described in U.S. Pat. No. 3,275,626, involves the conversion of the thiazolidine ring of a penicillin into the dihydrothiazine ring of a cephalosporin. The fused .beta.-lactam ring of the penicillin molecule remains intact during the conversion. This chemical conversion is carried out by heating a penicillin sulfoxide in the presence of an acidic reagent, such as acetic anhydride, to obtain predominantly a 7-acylamido-3-methyl-3-cephem-4-carboxylic acid ester (a desacetoxycephalosporanic acid) and a 7-acylamido-3-methyl-3-acyloxycepham-4-carboxylic acid ester. Also produced in the chemical conversion process is a 2-acyloxymethylpenicillin, otherwise designated as a 6-acylamido-2-methyl-2-acyloxymethylpenam-3-carboxylic acid.
U.S. Pat. No. 3,275,626 additionally discusses the possibility of converting a penicillin sulfoxide by heating it in the presence of any of various acidic reagents. The ultimate antibiotic substances which form from such reactions will depend to some extent upon the particular acid which is employed, with the substituents present in the acid as well as the particular structure and relative strength of the acid having some effect upon the products formed.
In carrying out the reaction of a penicillin sulfoxide ester with thionyl chloride, it has been found that the following products are obtained: ##SPC1##
It further has been found that the 2.beta.-chloromethyl-2.alpha.-methylpenam (I above) is unstable and gradually rearranges to the corresponding 3.alpha.-methyl-3.beta.-chlorocepham of the formula ##SPC2##
This rearrangement occurs at room temperature over a period of several days. The rearrangement can be greatly accelerated by subjecting the penam to an elevated temperature, for example, from about 50.degree.C. to about 100.degree.C., under which conditions the rearrangement can be accomplished in as little as 1 hour. Conversion to the corresponding 3.alpha.-methyl-3.beta.-chlorocepham can also be effected by maintaining the unstable penam in a suitable inert solvent on a chromatographic column for a period of from about 24 to about 72 hours and then eluting the cepham product from the column.
In accordance with this invention, it has now been discovered that it is possible to convert a 7-imido-3.beta.-hydroxycepham-3.alpha.-methyl-4-carboxylic acid ester having a structure such as (III) above to an active 3-methyl-3-cephem antibiotic, and, by ring-contraction, to a 2.alpha.-halomethylpenam-2.beta.-methyl (penicillin) ring structure and a 2.beta.-halomethylpenam-2.alpha.-methyl (pencillin) ring structure.